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Background: Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus. It may progress to respiratory failure, and a significant proportion of patients die. Preliminary data suggest that a high viral load of the SARS coronavirus is associated with adverse outcomes in the intensive care unit, but the relation of viral load to survival is unclear. Methods: We prospectively studied an inception cohort of 133 patients with virologically confirmed SARS who were admitted to 2 general acute care hospitals in Hong Kong from Mar. 24 to May 4, 2003. The patients were followed until death or for a minimum of 90 days. We used Cox proportional hazard modelling to analyze potential predictors of survival recorded at the time of presentation, including viral load from nasopharyngeal specimens (measured by quantitative reverse transcriptase polymerase chain reaction [PCR] of the SARS-associated coronavirus). Results: Thirty-two patients (24.1%) met the criteria for acute respiratory distress syndrome, and 24 patients (18.0%) died. The following baseline factors were independently associated with worse survival: older age (61-80 years) (adjusted hazard ratio [HR] 5.24, 95% confidence interval [CI] 2.03-13.53), presence of an active comorbid condition (adjusted HR 3.36, 95% CI 1.44-7.82) and higher initial viral load of SARS coronavirus, according to quantitative PCR of nasopharyngeal specimens (adjusted HR 1.21 per log10 increase in number of RNA copies per millilitre, 95% CI 1.06-1.39). Interpretation: We found preliminary evidence that higher initial viral load is independently associated with worse prognosis in SARS. Mortality data for patients with SARS should be interpreted in light of age, comorbidity and viral load. These considerations will be important in future studies of SARS. [ABSTRACT FROM AUTHOR]

Clinical deterioration during the course of community-acquired infections can occur as a result of an exaggerated immune response of the host towards the inciting pathogens, leading to immune-mediated tissue damage. Whether a surge in the peripheral lymphocyte count can be used as a surrogate marker indicating the onset of immunopathological tissue damage is not known. In this study, we report the clinical presentations and outcomes of a cohort of immunocompetent patients with non-tuberculous community acquired infections who experienced clinical deterioration during hospital stay ( n= 85). 12 (14.1%) patients had a surge in lymphocyte count preceding their clinical deteriorations, and their diagnoses included viral pneumonitis (4) , viral encephalitis (3) , scrub typhus (2) , leptospirosis (1) , brucellosis (1) , and dengue haemorrhagic fever (1) . The clinical manifestations during deterioration ranged from interstitial pneumonitis (6) , airway obstruction (1) , CNS disturbances (4) , and systemic capillary leak syndrome (1) , all of which were thought to represent immunopathological tissue damages. When compared with patients without lymphocyte surge, these patients were more likely to be infected with fastidious/viral pathogens (0 vs 12; p <0.05), in addition to having lower mean baseline lymphocyte counts (403±181 vs 1143±686 cells/μl; p <0.05). We postulate that the peripheral lymphocyte count may be a useful surrogate marker indicating the presence of immunopathological damage during clinical deterioration in certain infectious diseases. [ABSTRACT FROM AUTHOR]

Background Although the genome of severe acute respiratory syndrome coronavirus (SARS-CoV) has been sequenced and a possible animal reservoir identified, seroprevalence studies and mass screening for detection of subclinical and non-pneumonic infections are still lacking.Methods We cloned and purified the nucleocapsid protein and spike polypeptide of SARS-CoV and examined their immunogenicity with serum from patients with SARS-CoV pneumonia. An ELISA based on recombinant nucleocapsid protein for IgG detection was tested with serum from 149 healthy blood donors who donated 3 years previously and with serum positive for antibodies against SARS-CoV (by indirect immunofluorescence assay) from 106 patients with SARS-CoV pneumonia. The seroprevalence of SARS-CoV was studied with the ELISA in healthy blood donors who donated during the SARS outbreak in Hong Kong, non-pneumonic hospital inpatients, and symptom-free health-care workers. All positive samples were confirmed by two separate western-blot assays (with recombinant nucleocapsid protein and recombinant spike polypeptide).Findings Western-blot analysis showed that the nucleocapsid protein and spike polypeptide of SARS-CoV are highly immunogenic. The specificity of the IgG antibody test (ELISA with positive samples confirmed by the two western-blot assays) was 100%, and the sensitivity was 94·3%. Three of 400 healthy blood donors who donated during the SARS outbreak and one of 131 non-pneumonic paediatric inpatients were positive for IgG antibodies, confirmed by the two western-blot assays (total, 0·48% of our study population).Interpretation Our findings support the existence of subclinical or non-pneumonic SARS-CoV infections. Such infections are more common than SARS-CoV pneumonia in our locality. [Copyright &y& Elsevier]

Background: Pneumocystis jiroveci pneumonia (PCP) is an important opportunistic infection among immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV). The clinical presentation of PCP in immunosuppressed patients have been well-reported in the literature. However, the clinical importance of PCP manifesting in the setting of an immunorestitution disease (IRD), defined as an acute symptomatic or paradoxical deterioration of a (presumably) preexisting infection, which is temporally related to the recovery of the immune system and is due to immunopathological damage associated with the reversal of immunosuppressive processes, has received relatively little attention until recently. Case presentation: We aim to better define this unique clinical syndrome by reporting two cases of PCP manifesting acutely with respiratory failure during reversal of immunosuppression in non-HIV infected patients, and reviewed the relevant literature. We searched our databases for PCP cases manifesting in the context of IRD according to our predefined case definition, and reviewed the case notes retrospectively. A comprehensive search was performed using the Medline database of the National Library of Medicine for similar cases reported previously in the English literature in October 2003. A total of 28 non-HIV (excluding our present case) and 13 HIV-positive patients with PCP manifesting as immunorestitution disease (IRD) have been reported previously in the literature. During immunorestitution, a consistent rise in the median CD4 lymphocyte count (28/µL to 125/ µL), with a concomitant fall in the median HIV viral load (5.5 log10 copies/ml to 3.1 log10 copies/ml) was observed in HIV-positive patients who developed PCP. A similar upsurge in peripheral lymphocyte count was observed in our patients preceding the development of PCP, as well as in other non-HIV immunosuppressed patients reported in the literature. Conclusions: PCP manifesting as IRD may be more common than is generally appreciated. Serial monitoring of total lymphocyte or CD4 count could serve as a useful adjunct to facilitate the early diagnosis and pre-emptive treatment of this condition in a wide range of immunosuppressed hosts, especially in the presence of new pulmonary symptoms and/or radiographic abnormalities compatible with the diagnosis. [ABSTRACT FROM AUTHOR]

Trichuris trichiura is a worldwide problem affecting millions of people. We report an unusual case of intussusception caused by T. trichiura that mimics acute appendicitis. The literature on T. trichiura associated intussusception is reviewed. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the prevalence of patients with functional constipation to colorectal cancer.

A response by Ivan F. N. Hung and Kwok-Yung Yuen to a letter to the editor about the article "Dual Pneumococcal and Influenza Vaccination in Elderly Patients with Chronic Illnesses: Protective Benefits Overestimated?" in the previous issue is presented.

Background and Aim: We aimed to investigate the effect of metabolic dysfunction-associated steatotic liver disease (MASLD) on three-dose BNT162b2 immunogenicity to the omicron variant., Methods: Adult recipients of three doses of BNT162b2 were prospectively recruited between May and December 2021. The serology of the neutralizing antibody by live virus microneutralization (vMN) to the omicron variant was measured at baseline, day 180, and day 360 after the first dose. The primary outcome was seroconversion (vMN titer ≥ 10) at day 360. Exposure of interest was MASLD, defined as hepatic steatosis (controlled attenuation parameter ≥ 248 dB/m on transient elastography) plus at least one of five cardiometabolic risk factors. Subjects with prior COVID-19 were excluded. A multivariable logistic regression model was used to derive the adjusted odds ratio of seroconversion with MASLD by adjusting for age, sex, antibiotic use, and proton pump inhibitor use., Results: One hundred forty-eight BNT162b2 recipients (male: 48 [32.4%]; median age: 51.0 years [interquartile range, IQR: 44.5-57.3]) were recruited. The median time from the first dose to the third dose was 8.5 months (IQR: 7.9-8.9). MASLD subjects had a lower seroconversion rate than non-MASLD ones (89.6% vs 99.0%; P = 0.007). MASLD was the only independent risk factor for seroconversion (adjusted odds ratio: 0.051, 95% confidence interval: 0.002-0.440). Subgroup analysis of immunogenicity at 4 months after the third dose shows significantly lower vMN titer (13.06 [IQR: 7.69-22.20] vs 33.49 [IQR: 24.05-46.53]; P = 0.004) and seroconversion rate (76.9% vs 97.4%; P = 0.016) in MASLD than non-MASLD subjects, but not within 4 months from the third dose (vMN titer: 46.87 [IQR: 33.12-66.02] vs 41.86 [IQR: 34.47-50.91], P = 0.240; seroconversion rate: 94.3% vs 100%, P = 0.131)., Conclusion: Metabolic dysfunction-associated steatotic liver disease was a risk factor for poorer immunogenicity to the omicron variant, with a more pronounced waning effect compared among three-dose BNT162b2 recipients., (© 2024 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Proton pump inhibitors (PPIs) may increase the risk of COVID-19 among non-vaccinated subjects via various mechanisms, including gut dysbiosis. We aimed to investigate whether PPIs also affect the clinical outcomes of COVID-19 among vaccine recipients., Methods: This was a territory-wide cohort study of 3 272 286 vaccine recipients (aged ≥ 18 years) of ≥ 2 doses of either BNT162b2 or CoronaVac. Exclusion criteria included prior gastrointestinal surgery, immunocompromised status, and prior COVID-19. The primary outcome was COVID-19, and secondary outcomes included COVID-19-related hospitalization and severe infection (composite of intensive care unit admission, ventilatory support, and/or death). Covariates include age, sex, the Charlson Comorbidity Index, comorbidities, and concomitant medication use. Subjects were followed from index date (first dose of vaccination) until outcome occurrence, death, additional dose of vaccination, or March 31, 2022. Exposure was pre-vaccination PPI use (any prescription within 90 days before the index date). Propensity score (PS) matching and a Poisson regression model were used to estimate the adjusted incidence rate ratio (aIRR) of outcomes with PPI use., Results: Among 439 154 PS-matched two-dose vaccine recipients (mean age: 65.3 years; male: 45.7%) with a median follow-up of 6.8 months (interquartile range: 2.6-7.9), PPI exposure was associated with a higher risk of COVID-19 (aIRR: 1.08; 95% confidence interval [95% CI]: 1.05-1.10), hospitalization (aIRR: 1.20; 95% CI: 1.08-1.33), and severe infection (aIRR: 1.57; 95% CI: 1.24-1.98). Among 188 360 PS-matched three-dose vaccine recipients (mean age: 62.5 years; male: 49.0%; median follow-up: 9.1 months [interquartile range: 8.0-10.9]), PPIs were associated with higher infection risk (aIRR: 1.11; 95% CI: 1.08-1.15) but not other outcomes., Conclusions: Although PPI use was associated with a higher COVID-19 risk, severe infection was limited to two-dose but not three-dose vaccine recipients., (© 2024 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

CoronaVac immunogenicity decreases with time, and we aimed to investigate whether gut microbiota associate with longer-term immunogenicity of CoronaVac. This was a prospective cohort study recruiting two-dose CoronaVac recipients from three centres in Hong Kong. We collected blood samples at baseline and day 180 after the first dose and used chemiluminescence immunoassay to test for neutralizing antibodies (NAbs) against the receptor-binding domain (RBD) of wild-type SARS-CoV-2 virus. We performed shotgun metagenomic sequencing performed on baseline stool samples. The primary outcome was the NAb seroconversion rate (seropositivity defined as NAb ≥ 15AU/mL) at day 180. Linear discriminant analysis [LDA] effect size analysis was used to identify putative bacterial species and metabolic pathways. A univariate logistic regression model was used to derive the odds ratio (OR) of seropositivity with bacterial species. Of 119 CoronaVac recipients (median age: 53.4 years [IQR: 47.8-61.3]; male: 39 [32.8%]), only 8 (6.7%) remained seropositive at 6 months after vaccination. Bacteroides uniformis (log 10 LDA score = 4.39) and Bacteroides eggerthii (log 10 LDA score = 3.89) were significantly enriched in seropositive than seronegative participants. Seropositivity was associated with B. eggerthii (OR: 5.73; 95% CI: 1.32-29.55; p = 0.022) and B. uniformis with borderline significance (OR: 3.27; 95% CI: 0.73-14.72; p = 0.110). Additionally, B. uniformis was positively correlated with most enriched metabolic pathways in seropositive vaccinees, including the superpathway of adenosine nucleotide de novo biosynthesis I (log 10 LDA score = 2.88) and II (log 10 LDA score = 2.91), as well as pathways related to vitamin B biosynthesis, all of which are known to promote immune functions. In conclusion, certain gut bacterial species ( B. eggerthii and B. uniformis ) and metabolic pathways were associated with longer-term CoronaVac immunogenicity.

Reports of symptomatic rebound and/or test re-positivity among COVID-19 patients following the standard five-day treatment course of nirmatrelvir/ritonavir have sparked debates regarding optimal treatment timing and dosage. It is unclear whether initiating nirmatrelvir/ritonavir immediately after symptom onset would improve clinical outcomes and/or lead to post-treatment viral burden rebound due to inadequate viral clearance during treatment. Here we show that, by emulating a randomized target trial using real-world electronic medical record data from all 87,070 adult users of nirmatrelvir/ritonavir in Hong Kong between 16th March 2022 and 15th January 2023, early initiation of nirmatrelvir/ritonavir treatment (0 to 1 days after symptom onset or diagnosis) significantly reduced the incidence of 28-day all-cause mortality and hospitalization compared to delayed initiation (2 or more days) (absolute risk reduction [ARR]: 1.50% (95% confidence interval 1.17-1.80%); relative risk [RR]: 0.77 (0.73, 0.82)), but may be associated with a significant elevated risk of viral burden rebound (ARR: -1.08% (-1.55%, -0.46%)), although the latter estimates were associated with high uncertainty due to limited sample sizes. As such, patients should continue to initiate nirmatrelvir/ritonavir early after symptom onset or diagnosis to better protect against the more serious outcomes of hospitalization and mortality., (© 2023. The Author(s).)

Background: Viral rebound after nirmatrelvir-ritonavir treatment has implications for the clinical management and isolation of patients with COVID-19. We evaluated an unselected, population-wide cohort to identify the incidence of viral burden rebound and associated risk factors and clinical outcomes., Methods: We did a retrospective cohort study of hospitalised patients with a confirmed diagnosis of COVID-19 in Hong Kong, China, for an observation period from Feb 26 to July 3, 2022 (during the omicron BA.2.2 variant wave). Adult patients (age ≥18 years) admitted 3 days before or after a positive COVID-19 test were selected from medical records held by the Hospital Authority of Hong Kong. We included patients with non-oxygen-dependent COVID-19 at baseline receiving either molnupiravir (800 mg twice a day for 5 days), nirmatrelvir-ritonavir (nirmatrelvir 300 mg with ritonavir 100 mg twice a day for 5 days), or no oral antiviral treatment (control group). Viral burden rebound was defined as a reduction in cycle threshold (Ct) value (≥3) on quantitative RT-PCR test between two consecutive measurements, with such decrease sustained in an immediately subsequent Ct measurement (for those patients with ≥3 Ct measurements). Logistic regression models were used to identify prognostic factors for viral burden rebound, and to assess associations between viral burden rebound and a composite clinical outcome of mortality, intensive care unit admission, and invasive mechanical ventilation initiation, stratified by treatment group., Findings: We included 4592 hospitalised patients with non-oxygen-dependent COVID-19 (1998 [43·5%] women and 2594 [56·5%] men). During the omicron BA.2.2 wave, viral burden rebound occurred in 16 of 242 patients (6·6% [95% CI 4·1-10·5]) receiving nirmatrelvir-ritonavir, 27 of 563 (4·8% [3·3-6·9]) receiving molnupiravir, and 170 of 3787 (4·5% [3·9-5·2]) in the control group. The incidence of viral burden rebound did not differ significantly across the three groups. Immunocompromised status was associated with increased odds of viral burden rebound, regardless of antiviral treatment (nirmatrelvir-ritonavir: odds ratio [OR] 7·37 [95% CI 2·56-21·26], p=0·0002; molnupiravir: 3·05 [1·28-7·25], p=0·012; control: 2·21 [1·50-3·27], p<0·0001). Among patients receiving nirmatrelvir-ritonavir, the odds of viral burden rebound were higher in those aged 18-65 years (vs >65 years; 3·09 [1·00-9·53], p=0·050), those with high comorbidity burden (score >6 on the Charlson Comorbidity Index; 6·02 [2·09-17·38], p=0·0009), and those concomitantly taking corticosteroids (7·51 [1·67-33·82], p=0·0086); whereas the odds were lower in those who were not fully vaccinated (0·16 [0·04-0·67], p=0·012). In patients receiving molnupiravir, those aged 18-65 years (2·68 [1·09-6·58], p=0·032) or on concomitant corticosteroids (3·11 [1·23-7·82], p=0·016) had increased odds of viral burden rebound. We found no association between viral burden rebound and occurrence of the composite clinical outcome from day 5 of follow-up (nirmatrelvir-ritonavir: adjusted OR 1·90 [0·48-7·59], p=0·36; molnupiravir: 1·05 [0·39-2·84], p=0·92; control: 1·27 [0·89-1·80], p=0·18)., Interpretation: Viral burden rebound rates are similar between patients with antiviral treatment and those without. Importantly, viral burden rebound was not associated with adverse clinical outcomes., Funding: Health and Medical Research Fund, Health Bureau, The Government of the Hong Kong Special Administrative Region, China., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests CKHW reports receipt of research funding from the EuroQoL Group Research Foundation, AstraZeneca, and Boehringer Ingelheim, unrelated to this work. BJC reports honoraria from AstraZeneca, Fosun Pharma, GlaxoSmithKline, Moderna, Pfizer, Roche, and Sanofi Pasteur. BJC has provided scientific advice to Pfizer and AstraZeneca on issues related to disease burden and vaccine effectiveness; BJC has not provided scientific advice to Pfizer or AstraZeneca related to COVID-19 antiviral effectiveness, and has not received any funding from Pfizer or AstraZeneca for any research on antiviral effectiveness including the current work. IFNH has received speaker honoraria from MSD and was an advisory board member for Pfizer, Gilead, Fosun, MSD, and AstraZeneca. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results., Objectives: We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19., Methods: Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group., Results: Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent., Conclusions: Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079)., Competing Interests: Funding Support and Author Disclosures Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, and Abbott; has served as a consultant to Daiichi-Sankyo, Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, and Millennia Biopharma; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; his daughter is an employee at IQVIA; and his employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Dr Farkouh has received institutional research grants from Amgen, AstraZeneca, Novo Nordisk, and Novartis; has received consulting fees from Otitopic; and has received honoraria from Novo Nordisk. Dr Lala has received consulting fees from Merck and Bioventrix; has received honoraria from Zoll Medical and Novartis; has served on an advisory board for Sequana Medical; and is the Deputy Editor for the Journal of Cardiac Failure. Dr Moreno has received honoraria from Amgen, Cuquerela Medical, and Gafney; has received payment for expert testimony from Koskoff, Koskoff & Dominus, Dallas W. Hartman, and Riscassi & Davis PC; and has stock options in Provisio. Dr Goodman has received institutional research grants from Bristol Myers Squibb/Pfizer Alliance, Bayer, and Boehringer Ingelheim; has received consulting fees from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Ferring Pharmaceuticals, HLS Therapeutics, Novartis, Pendopharm/Pharmascience, Pfizer, Regeneron, and Sanofi; has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, and Servier; has served on Data Safety and Monitoring boards for Daiichi-Sankyo/American Regent and Novo Nordisk A/C; has served on advisory boards for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, and Tolmar Pharmaceuticals; has a leadership role in the Novartis Council for Heart Health (unpaid); and otherwise has received salary support or honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and the TIMI Study Group (Brigham Health). Dr Ricalde has received consulting fees from Medtronic, Servier, and Boston Scientific; has received honoraria from Medtronic, Pfizer, Merck, Boston Scientific, Biosensors, and Bayer; has served on an advisory board for Medtronic; and has leadership roles in SOLACI and Kardiologen. Dr Payro has received consulting fees from Bayer Mexico; has received honoraria from Bayer, Merck, AstraZeneca, Medtronic, and Viatris; has received payments for expert testimony from Bayer; has received travel support from AstraZeneca; has served on an advisory board for Bayer; and his institution has received equipment donated from AstraZeneca. Dr Castellano has received consulting fees and honoraria from Ferrer International, Servier, and Daiichi-Sankyo; and has received travel support from Ferrer International. Dr Hung has served as an advisory board member for Pfizer, Merck, AstraZeneca, Fosun, and Gilead. Dr Nadkarni has received consulting fees from Renalytix, Variant Bio, Qiming Capital, Menarini Health, Daiichi-Sankyo, BioVie, and Cambridge Health; has received honoraria from Daiichi-Sankyo and Menarini Health; has patents for automatic disease diagnoses using longitudinal medical record data, methods, and apparatus for diagnosis of progressive kidney function decline using a machine learning model, electronic phenotyping technique for diagnosing chronic kidney disease, deep learning to identify biventricular structure and function, fusion models for identification of pulmonary embolism, and SparTeN: a novel spatio-temporal deep learning model; has served on a Data Safety and Monitoring Board for CRIC OSMB; has leadership roles for Renalytix scientific advisory board, Pensive Health scientific advisory board, and ASN Augmented Intelligence and Digital Health Committee; has ownership interests in Renalytix, Data2Wisdom LLC, Verici Dx, Nexus I Connect, and Pensieve Health; and his institution receives royalties from Renalytix. Dr Goday has received the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the Canadian Institutes of Health Research. Dr Furtado has received institutional research grants from AstraZeneca, CytoDin, Pfizer, Servier, Amgen, Alliar Diagnostics, and the Brazilian Ministry of Health; has received consulting fees from Biomm and Bayer; has received honoraria from AstraZeneca, Bayer, Servier, and Pfizer; and has received travel support from Servier, AstraZeneca, and Bayer. Dr Granada has received consulting fees, travel support, and stock from Cogent Technologies Corp; and has received stock from Kutai. Dr Contreras has served as a consultant for Merck, CVRx, Novodisk, and Boehringer Ingelheim; and has received educational grants from Alnylam Pharmaceuticals and AstraZeneca. Dr Bhatt has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, Cincor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89bio; has received royalties from Elsevier; has received consultant fees from Broadview Ventures and McKinsey; has received honoraria from the American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, Rutgers University, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, WebMD, Wiley, Society of Cardiovascular Patient Care; has received fees from expert testimony from the Arnold and Porter law firm; has received travel support from the American College of Cardiology, Society of Cardiovascular Patient Care, American Heart Association; has a patent for otagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; has participated on a data safety monitoring board or advisory board for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, AngioWave, Baim Institute, Bayer, Boehringer Ingelheim, Boston Scientific, Cardax, CellProthera, Cereno Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Elsevier Practice Update Cardiology, Janssen, Level Ex, Mayo Clinic, Medscape Cardiology, Merck, Mount Sinai School of Medicine, MyoKardia, NirvaMed, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Population Health Research Institute, and Stasys; serves as a trustee or director for American College of Cardiology, AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft; has ownership interests in AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; has other interests in Clinical Cardiology, the NCDR-ACTION Registry Steering Committee; has conducted unfunded research with FlowCo and Takeda, Contego Medical, American Heart Association Quality Oversight Committee, Inaugural Chair, VA CART Research and Publications Committee; and has been a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott), Phillips SpectraWAVE, Svelte, and Vascular Solutions. Dr Fuster declares that he raised $7 million from patients for this study granted to Mount Sinai Heart, unrelated to industry. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Understanding the trend of global antifungal agent consumption could assist with identification of global healthcare policy inadequacies and promote accessibility and availability of antifungal agents., Methods: Using pharmaceutical sales data from the IQVIA-multinational integrated data analysis system database, we assessed use of systemic antifungal agents in humans in 27 middle- and 38 high-income countries from 2008 through 2018., Results: Consumption of systemic antifungal agents increased from 0.50 (in 2008) to 0.92 defined daily dose (DDD)/1000 inhabitants/day (in 2018), with a compound annual growth rate of 6.2%. High-income countries remain major consumers of antifungal agents with large variance in quantities consumed, with a gradual decline in consumption in recent years. Consumption in middle-income countries increased. Itraconazole (0.32 DDD/1000 inhabitants/day), terbinafine (0.30 DDD/1000 inhabitants/day), and fluconazole (0.23 DDD/1000 inhabitants/day) were the most commonly used antifungal agents in middle- and high-income countries in 2018. Following incorporation into the World Health Organization Essential Medicines List, itraconazole consumption in middle-income countries surged. Consumption of ketoconazole slowly declined, with 5.04% annual decrease, probably due to labelling changes in 2013 to reflect hepatotoxicity concerns. The use of polyenes (0.004 DDD/1000 inhabitants/day) and echinocandins (0.003 DDD/1000 inhabitants/day) were lowest among all the antifungal drug classes., Conclusion: Global consumption of triazoles and terbinafine has gradually increased in middle- and high-income countries. Life-saving antifungal agents, including echinocandins and polyenes, are available only parenterally and may be underutilized, mainly in middle-income countries. Future research on country-specific epidemiology is warranted to guide health policy coordination to ensure equitable access to appropriate use of antifungal agents., (© 2022. The Author(s).)

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral loads change rapidly following symptom onset, so to assess antivirals it is important to understand the natural history and patient factors influencing this. We undertook an individual patient-level meta-analysis of SARS-CoV-2 viral dynamics in humans to describe viral dynamics and estimate the effects of antivirals used to date. This systematic review identified case reports, case series, and clinical trial data from publications between January 1, 2020, and May 31, 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A multivariable Cox proportional hazards (Cox-PH) regression model of time to viral clearance was fitted to respiratory and stool samples. A simplified four parameter nonlinear mixed-effects (NLME) model was fitted to viral load trajectories in all sampling sites and covariate modeling of respiratory viral dynamics was performed to quantify time-dependent drug effects. Patient-level data from 645 individuals (age 1 month to 100 years) with 6,316 viral loads were extracted. Model-based simulations of viral load trajectories in samples from the upper and lower respiratory tract, stool, blood, urine, ocular secretions, and breast milk were generated. Cox-PH modeling showed longer time to viral clearance in older patients, men, and those with more severe disease. Remdesivir was associated with faster viral clearance (adjusted hazard ratio (AHR) = 9.19, P < 0.001), as well as interferon, particularly when combined with ribavirin (AHR = 2.2, P = 0.015; AHR = 6.04, P = 0.006). Combination therapy should be further investigated. A viral dynamic dataset and NLME model for designing and analyzing antiviral trials has been established., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Nine years after the introduction of pneumococcal conjugate vaccine (PCV) in the United States, Hong Kong (HK) introduced the vaccine to its universal childhood immunisation programme in 2009. We aimed to assess the impact of childhood PCV immunisation on all-cause pneumonia (ACP) admissions among the overall population of HK., Methods: In this population-based interrupted time series analysis, we used territory-wide population-representative electronic health records in HK to evaluate the vaccine impact. We identified hospitalised patients with a diagnosis of pneumonia from any cause between 2004 and 2017. We applied segmented Poisson regression to assess the gradual change in the monthly incidence of ACP admissions between pre- and post-vaccination periods. Negative outcome control, subgroup and sensitivity analyses were used to test the robustness of the main analysis., Findings: Over the 14-year study period, a total of 587,607 ACP episodes were identified among 357,950 patients. The monthly age-standardised incidence of ACP fluctuated between 33.42 and 87.44 per 100,000-persons. There was a marginal decreasing trend in pneumonia admissions after PCV introduction among overall population (incidence rate ratio [IRR]: 0·9965, 95% confidence interval [CI]: 0·9932-0·9998), and older adults (≥65 years, IRR: 0·9928, 95% CI: 0·9904-0·9953) but not in younger age groups., Interpretation: There was a marginally declining trend of overall ACP admissions in HK up to eight years after childhood PCV introduction. The significance disappeared when fitting sensitivity analyses. The results indicate the complexities of using non-specific endpoints for measuring vaccine effect and the necessity of enhancing serotype surveillance systems for replacement monitoring., Funding: Health and Medical Research Fund, Food and Health Bureau of the Government of Hong Kong (Reference number: 18171272)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. X Li reports research and educational grants from Janssen, Pfizer, internal grants from University of Hong Kong, consulting fees from MSD, outside the submitted work. Dr. EW Chan reports other from Hospital Authority, grants from Research Grants Council (RGC, Hong Kong), grants from Research Fund Secretariat of the Food and Health Bureau, grants from National Natural Science Fund of China, grants from Wellcome Trust, grants from Bayer, grants from Bristol-Myers Squibb, grants from Pfizer, grants from Janssen, grants from Amgen, grants from Takeda, grants from Narcotics Division of the Security Bureau of HKSAR, outside the submitted work. Dr. IP has received research grants from Research Grants Council (RGC, Hong Kong) and Health and Medical Research Fund (HMRF), outside the submitted work. Professor BJ Cowling reports personal fees from Sanofi Pasteur, personal fees from Roche, outside the submitted work. Professor ICK Wong reports grants from Amgen, grants from Bristol-Myers Squibb, grants from Pfizer, grants from Janssen, grants from Bayer, grants from Bayer, grants from Novartis, grants from the Hong Kong Research Grants Council, grants from the Hong Kong Health and Medical Research Fund, grants from National Institute for Health Research in England, grants from European Commission, grants from National Health and Medical Research Council in Australia, outside the submitted work; and also received speaker fee from Janssen and Medice in previous 3 years. The other authors declared no conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose of Review: Coronavirus disease 2019 (COVID-19) is a highly contagious and potentially lethal pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). No specific antiviral treatment is currently available. The purpose of this review is to highlight the main repurposed drug treatments with in-vitro or in-vivo efficacy against the SARS-CoV-2., Recent Findings: Recent clinical trials suggested remdesivir, IFN-β-1b and favipiravir have potential clinical and/or virological benefits on patients with COVID-19. Short course of stress dose of corticosteroids might be used as adjunctive treatment to patients who are late presenters with cytokine storm. Convalescent plasma from recovered COVID-19 patients with high neutralizing antibody might also be beneficial in the treatment of severe disease., Summary: Early effective antiviral therapy in COVID-19 patients will suppress the SARS-CoV-2 viral load. Adjunctive therapy with corticosteroid and convalescent plasma might further ameliorate the cytokine response. Further randomized clinical trials of combination therapy are needed.

Viral hepatitis can cause significant maternal and neonatal morbidity and mortality. Hepatitis A and E mainly present as acute hepatitis during pregnancy, while hepatitis C and D are usually found as chronic infection in pregnant women. Hepatitis A remains self-limiting during pregnancy while hepatitis E has a higher prevalence and manifests with a rigorous course in pregnant women. Screening of hepatitis C during pregnancy and its subsequent management during pregnancy are still a debatable topic. New treatments of hepatitis C and E require further evaluation for use in pregnancy. This review summarizes the prevalence, clinical manifestations, maternal, foetal and neonatal effects, and the management of hepatitis A, C, D and E viral infection during pregnancy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Ltd.)

Background: To describe the infection control strategy to achieve zero nosocomial transmission of symptomatic coronavirus disease (COVID-19) due to SARS-CoV-2 during the prepandemic phase (the first 72 days after announcement of pneumonia cases in Wuhan) in Hong Kong., Methods: Administrative support with the aim of zero nosocomial transmission by reducing elective clinical services, decanting wards, mobilizing isolation facilities, providing adequate personal protective equipment, coordinating laboratory network for rapid molecular diagnosis under 4-tier active surveillance for hospitalized patients and outpatients, and organizing staff forum and training was implemented under the framework of preparedness plan in Hospital Authority. The trend of SARS-CoV-2 in the first 72 days was compared with that of SARS-CoV 2003., Results: Up to day 72 of the epidemic, 130 (0.40%) of 32,443 patients being screened confirmed to have SARS-CoV-2 by reverse transcription polymerase chain reaction. Compared with SARS outbreak in 2003, the SARS-CoV-2 case load constituted 8.9% (130 SARS-CoV-2/1458 SARS-CoV) of SARS-CoV infected cases at day 72 of the outbreak. The incidences of nosocomial acquisition of SARS-CoV per 1,000 SARS-patient-day and per 100 SARS-patient-admission were 7.9 and 16.9, respectively, which were significantly higher than the corresponding incidences of SARS-CoV-2 (zero infection, P <.001)., Conclusions: Administrative support to infection control could minimize the risk of nosocomial transmission of SARS-CoV-2., (Copyright © 2020 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has been characterized by fever, respiratory, and gastrointestinal symptoms as well as shedding of virus RNA into feces. We performed a systematic review and meta-analysis of published gastrointestinal symptoms and detection of virus in stool and also summarized data from a cohort of patients with COVID-19 in Hong Kong., Methods: We collected data from the cohort of patients with COVID-19 in Hong Kong (N = 59; diagnosis from February 2 through February 29, 2020),and searched PubMed, Embase, Cochrane, and 3 Chinese databases through March 11, 2020, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We analyzed pooled data on the prevalence of overall and individual gastrointestinal symptoms (loss of appetite, nausea, vomiting, diarrhea, and abdominal pain or discomfort) using a random effects model., Results: Among the 59 patients with COVID-19 in Hong Kong, 15 patients (25.4%) had gastrointestinal symptoms, and 9 patients (15.3%) had stool that tested positive for virus RNA. Stool viral RNA was detected in 38.5% and 8.7% among those with and without diarrhea, respectively (P = .02). The median fecal viral load was 5.1 log 10 copies per milliliter in patients with diarrhea vs 3.9 log 10 copies per milliliter in patients without diarrhea (P = .06). In a meta-analysis of 60 studies comprising 4243 patients, the pooled prevalence of all gastrointestinal symptoms was 17.6% (95% confidence interval [CI], 12.3-24.5); 11.8% of patients with nonsevere COVID-19 had gastrointestinal symptoms (95% CI, 4.1-29.1), and 17.1% of patients with severe COVID-19 had gastrointestinal symptoms (95% CI, 6.9-36.7). In the meta-analysis, the pooled prevalence of stool samples that were positive for virus RNA was 48.1% (95% CI, 38.3-57.9); of these samples, 70.3% of those collected after loss of virus from respiratory specimens tested positive for the virus (95% CI, 49.6-85.1)., Conclusions: In an analysis of data from the Hong Kong cohort of patients with COVID-19 and a meta-analysis of findings from publications, we found that 17.6% of patients with COVID-19 had gastrointestinal symptoms. Virus RNA was detected in stool samples from 48.1% patients, even in stool collected after respiratory samples had negative test results. Health care workers should therefore exercise caution in collecting fecal samples or performing endoscopic procedures in patients with COVID-19, even during patient recovery., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Linked color imaging (LCI) is a newly available image-enhanced endoscopy (IEE) system that emphasizes the red mucosal color. No study has yet compared LCI with other available IEE systems. Our aim was to investigate polyp detection rates using LCI compared with narrow-band imaging (NBI)., Methods: This is a prospective randomized tandem colonoscopy study. Eligible patients who underwent colonoscopy for symptoms or screening/surveillance were randomized in a 1:1 ratio to receive tandem colonoscopy with both colonoscope withdrawals using LCI or NBI. The primary outcome was the polyp detection rate., Results: Two hundred seventy-two patients were randomized (mean age, 62 years; 48.2% male; colonoscopy for symptoms, 72.8%) with 136 in each arm. During the first colonoscopy, the polyp detection rate (71.3% vs 55.9%; P = .008), serrated lesion detection rate (34.6% vs 22.1%; P = .02), and mean number of polyps detected (2.04 vs 1.35; P = .02) were significantly higher in the NBI group than in the LCI group. There was also a trend of higher adenoma detection rate in the NBI group compared with the LCI group (51.5% vs 39.7%, respectively; P = .05). Multivariable analysis confirmed that use of NBI (adjusted odds ratio, 1.99; 95% confidence interval, 1.09-3.68) and withdrawal time >8 minutes (adjusted odds ratio, 5.11; 95% confidence interval, 2.79-9.67) were associated with polyp detection. Overall, 20.5% of polyps and 18.1% of adenomas were missed by the first colonoscopy, but there was no significant difference in the miss rates between the 2 groups., Conclusion: NBI was significantly better than LCI for colorectal polyp detection. However, both LCI and NBI missed 20.5% of polyps. (Clinical trial registration number: NCT03336359.)., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is associated with increased severity of influenza infection. However, the underlying mechanism is largely unknown., Methods: We employed a mouse model with diet-induced obesity (DIO) to study the innate immune responses induced by influenza virus., Results: The lungs of DIO mice were heavily affected by obesity-associated chronic systemic inflammation with a significant increase in inflammatory cytokines/chemokines. Concurrently, lipid immune mediator prostaglandin E2 (PGE2) was also significantly elevated in DIO mice. However, the DIO mice mounted a blunted and delayed upregulation of mRNA and protein concentrations of interferon-β and inflammatory cytokines/chemokines upon A(H1N1)pdm09 virus (H1N1/415742Md) challenge compared with those of lean mice. PGE2 concentrations were significantly higher in the lungs of DIO mice compared to that of lean mice postchallenge. Treatment with paracetamol in challenged DIO mice significantly enhanced the expression of interferon-α/β and cytokine genes at days 1 and 3 postinfection compared with that of untreated DIO mice. Furthermore, paracetamol treatment alone started 3 days before virus challenge and continued until 6 days postchallenge ameliorated the severity of a lethal H1N1/415742Md infection in DIO mice with improved survival., Conclusions: Impaired innate response to influenza in DIO mice is associated with elevated PGE2, which could be restored to some degree by paracetamol treatment., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Melioidosis, although endemic in many parts of Southeast Asia, has not been systematically studied in Hong Kong, which is a predominantly urban area located in the subtropics. This review describes the early outbreaks of melioidosis in captive animals in Hong Kong in the 1970s, as well as the early reports of human clinical cases in the 1980s. A review of all hospitalized human cases of culture-confirmed melioidosis in the last twenty years showed an increasing trend in the incidence of the disease, with significant mortality observed. The lack of awareness of this disease among local physicians, the delay in laboratory diagnosis and the lack of epidemiological surveillance are among the greatest challenges of managing melioidosis in the territory.

Objectives: We assessed the immunological response of hospitalized adult patients with rhinovirus infection, including critically-ill patients., Methods: The differential white blood cell (WBC) count and the levels of 29 plasma cytokines/chemokines were compared between 50 adult hospitalized patients with rhinovirus infection and 100 age-matched controls with influenza virus infection., Results: The demographics and comorbidities were similar between rhinovirus and influenza patients, but severe disease was more common for the rhinovirus cohort. Rhinovirus patients had significantly higher WBC counts than influenza patients, especially for eosinophil (P = 3.1 × 10 -8 ). The level of the T H 2 cytokine IL-5 was significantly higher among rhinovirus patients, while the levels of 9 other cytokines/chemokines were significantly lower among rhinovirus patients. The levels of CXCL-10 (IP-10), CCL-2 (MCP-1), IFN-α2, IFN-γ, IL-10, and IL-15 remained significantly lower among rhinovirus patients after correction for multiple comparisons. Notably, CXCL-10 had the highest area under the receiver operating characteristic curve (AUC) in differentiating rhinovirus from influenza patients (AUC, 0.918). In the patient subgroup without asthma, the difference in the WBC count and cytokine/chemokine levels between rhinovirus and influenza patients remained statistically significant., Conclusions: Rhinovirus infection was characterized by a prominent T H 2 response, even in patients without asthma. CXCL-10 (IP-10) is a potential biomarker in differentiating rhinovirus from influenza infection., (Copyright © 2018 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Background: Influenza causes excessive hospitalizations and deaths. The study assessed the efficacy and safety of a clarithromycin-naproxen-oseltamivir combination for treatment of serious influenza., Methods: From February to April 2015, we conducted a prospective open-label, randomized, controlled trial. Adult patients hospitalized for A(H3N2) influenza were randomly assigned to a 2-day combination of clarithromycin 500 mg, naproxen 200 mg, and oseltamivir 75 mg twice daily, followed by 3 days of oseltamivir or to oseltamivir 75 mg twice daily without placebo for 5 days as a control method (1:1). The primary end point was 30-day mortality. The secondary end points were 90-day mortality, serial nasopharyngeal aspirate (NPA) virus titer, percentage of neuraminidase-inhibitor-resistant A(H3N2) virus (NIRV) quasispecies, pneumonia severity index (PSI), and duration of hospital stay., Results: Among the 217 patients with influenza A(H3N2) enrolled, 107 were randomly assigned to the combination treatment. The median age was 80 years, and 53.5% were men. Adverse events were uncommon. Ten patients died during the 30-day follow-up. The combination treatment was associated with lower 30-day mortality (P = .01), less frequent high dependency unit admission (P = .009), and shorter hospital stay (P < .0001). The virus titer and PSI (days 1-3; P < .01) and the NPA specimens with NIRV quasispecies ≥ 5% (days 1-2; P < .01) were significantly lower in the combination treatment group. Multivariate analysis showed that combination treatment was the only independent factor associated with lower 30-day mortality (OR, 0.06; 95% CI, 0.004-0.94; P = .04)., Conclusions: Combination treatment reduced both 30- and 90-day mortality and length of hospital stay. Further study of the antiviral and immunomodulatory effects of this combination treatment of severe influenza is warranted., Trial Registry: BioMed Central; No.: ISRCTN11273879 DOI 10.1186/ISRCTN11273879; URL: www.isrctn.com/ISRCTN11273879., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Oncovirus-associated malignancies are potentially preventable diseases with major public health significance. Human polyomaviruses (HPyVs) may be associated with oncogenesis or symptomatic illnesses in immunocompromised patients, but the site of viral shedding of most recently discovered HPyVs remains obscure. Using real-time PCR assay using specific primers targeting the HPyV6 large tumor antigen gene, we detected a phylogenetically distinct HPyV6 which was highly prevalent in the bile samples of patients with malignant biliary obstruction (18.8%) and acute gallstone cholangitis (5.5%). The prevalence rate and mean viral load of this HPyV6 were highest in the cholangiocarcinoma subgroup (27.6% and 2.41 × 10 4 copies/ml). These findings were confirmed with another real-time PCR assay using specific primers targeting the HPyV6 viral capsid protein 2 gene. These bile HPyV6 strains may represent a novel clade of HPyV6 as they formed a distinct cluster from the other HPyV6s and exhibited >2% differences in amino acid sequences in their major proteins. While HPyV6 was unlikely the cause of the patients' acute symptoms and liver dysfunction, the virus may be related to immunosuppression in patients with malignancy and/or important in the oncogenesis of cholangiocarcinoma in patients without coinfection with other oncogenic microbes. Further studies to ascertain a causative role of HPyV6 in cholangiocarcinoma should be conducted., (Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Early diagnosis of acute community-acquired pneumonia (CAP) is important in patient triage and treatment decisions. To identify biomarkers that distinguish patients with CAP from non-CAP controls, we conducted an untargeted global metabolome analysis for plasma samples from 142 patients with CAP (CAP cases) and 97 without CAP (non-CAP controls). Thirteen lipid metabolites could discriminate between CAP cases and non-CAP controls with area-under-the-receiver-operating-characteristic curve of >0.8 (P ≤ 10(-9)). The levels of glycosphingolipids, sphingomyelins, lysophosphatidylcholines and L-palmitoylcarnitine were higher, while the levels of lysophosphatidylethanolamines were lower in the CAP cases than those in non-CAP controls. All 13 metabolites could distinguish CAP cases from the non-infection, extrapulmonary infection and non-CAP respiratory tract infection subgroups. The levels of trihexosylceramide (d18:1/16:0) were higher, while the levels of lysophosphatidylethanolamines were lower, in the fatal than those of non-fatal CAP cases. Our findings suggest that lipid metabolites are potential diagnostic and prognostic biomarkers for CAP., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Human rhinovirus (HRV) is frequently detected in patients with respiratory tract infection. However, the full clinical spectrum of HRV infection in critically ill patients is not well characterized., Objective: To evaluate the clinical and virological characteristics of critically ill patients with HRV infection., Study Design: HRV-specific reverse transcription-polymerase chain reaction (RT-PCR) was performed on nasopharyngeal aspirate (NPA) specimens from 294 adult patients who required admission into the intensive care unit (ICU). Clinical characteristics were analyzed. HRV genotyping using the 5'UTR-VP4-VP2 region was performed., Results: HRV was detected in NPA specimens of 22 patients (7.5%) by RT-PCR. Dyspnea was the most common presenting symptom (16/22; 72.7%), but seizure also occurred in 5 (22.7%) patients. Exacerbation of underlying disease occurred in 12 (54.5%) patients. Four (18.2%) patients died, and HRV was considered to play a role as the cause of death in 3 patients. Thirteen (59.1%) patients had pneumonia, and the most common radiological finding was consolidation (6/13; 46.2%). Streptococcus pneumoniae was the most common co-pathogen among patients with pneumonia. Among the 9 patients without pneumonia, 3 patients had exacerbation of underlying lung diseases, 3 patients had acute pulmonary edema, 2 patients with diabetes mellitus had acute complications from poor glycemic control, and 1 patient had status epilepticus. HRV-A was the most common species (64.3%), but there was no clear relationship between HRV species and clinical presentation., Conclusion: Both pulmonary and extrapulmonary complications of HRV were common in critically ill patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: Stringent measures have been implemented in Hong Kong to prevent human infections due to avian influenza viruses (AIVs). Here, we report the seroprevalence of AIVs among high risk population., Methods: In this prospective study, blood samples were collected in October and November 2013 and in July 2014 from workers at live poultry market (LPM) and pig/cattle slaughterhouse (SH) in Hong Kong. Serum antibody titers against A(H5N1), A(H7N9) and A(H9N2) were determined., Results: When an hemagglutination inhibition (HI) titer of 40 was used as the cutoff, the A(H5N1) seropositive rate among LPM workers increased from 0% in 2013 to 37.8% in 2014 (P < 0.001) and the A(H9N2) seropositive rate increased from 10% to 55.6% (P < 0.001). There was no significant increase in A(H7N9) seropositive rate for LPM workers irrespective of cutoff titer. For SH workers, there was no significant increase in HI titer for any AIVs. Significantly more LPM workers had a ≥4-fold increase in A(H5N1) HI titer from 2013 to 2014 than SH workers (60% vs 8.3%, P = 0.020)., Conclusions: There was a significant increase of serum A(H5N1) and A(H9N2) HI titers among Hong Kong LPM workers between 2013 and 2014. Although we cannot exclude some degree of antibody cross-reactivity with other influenza viruses, our results suggest the occurrence of subclinical AIV infections in this population., (Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Although previous studies have reported the use of metabolomics for Mycobacterium species differentiation, little is known about the potential of extracellular metabolites of Mycobacterium tuberculosis (MTB) as specific biomarkers. Using an optimized ultrahigh performance liquid chromatography-electrospray ionization-quadruple time of flight-mass spectrometry (UHPLC-ESI-Q-TOF-MS) platform, we characterized the extracellular metabolomes of culture supernatant of nine MTB strains and nine non-tuberculous Mycobacterium (NTM) strains (four M. avium complex, one M. bovis Bacillus Calmette-Guérin (BCG), one M. chelonae, one M. fortuitum and two M. kansasii). Principal component analysis readily distinguished the metabolomes between MTB and NTM. Using multivariate and univariate analysis, 24 metabolites with significantly higher levels in MTB were identified. While seven metabolites were identified by tandem mass spectrometry (MS/MS), the other 17 metabolites were unidentified by MS/MS against database matching, suggesting that they may be potentially novel compounds. One metabolite was identified as dexpanthenol, the alcohol analog of pantothenic acid (vitamin B5), which was not known to be produced by bacteria previously. Four metabolites were identified as 1-tuberculosinyladenosine (1-TbAd), a product of the virulence-associated enzyme Rv3378c, and three previously undescribed derivatives of 1-TbAd. Two derivatives differ from 1-TbAd by the ribose group of the nucleoside while the other likely differs by the base. The remaining two metabolites were identified as a tetrapeptide, Val-His-Glu-His, and a monoacylglycerophosphoglycerol, phosphatidylglycerol (PG) (16∶0/0∶0), respectively. Further studies on the chemical structure and biosynthetic pathway of these MTB-specific metabolites would help understand their biological functions. Studies on clinical samples from tuberculosis patients are required to explore for their potential role as diagnostic biomarkers.

In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) caused one of the most devastating epidemics known to the developed world. There were two important lessons from this epidemic. Firstly, coronaviruses, in addition to influenza viruses, can cause severe and rapidly spreading human infections. Secondly, bats can serve as the origin and natural animal reservoir of deadly human viruses. Since then, researchers around the world, especially those in Asia where SARS-CoV was first identified, have turned their focus to find novel coronaviruses infecting humans, bats, and other animals. Two human coronaviruses, HCoV-HKU1 and HCoV-NL63, were identified shortly after the SARS-CoV epidemic as common causes of human respiratory tract infections. In 2012, a novel human coronavirus, now called Middle East respiratory syndrome coronavirus (MERS-CoV), has emerged in the Middle East to cause fatal human infections in three continents. MERS-CoV human infection is similar to SARS-CoV in having a high fatality rate and the ability to spread from person to person which resulted in secondary cases among close contacts including healthcare workers without travel history to the Middle East. Both viruses also have close relationships with bat coronaviruses. New cases of MERS-CoV infection in humans continue to occur with the origins of the virus still unknown in many cases. A multifaceted approach is necessary to control this evolving MERS-CoV outbreak. Source identification requires detailed epidemiological studies of the infected patients and enhanced surveillance of MERS-CoV or similar coronaviruses in humans and animals. Early diagnosis of infected patients and appropriate infection control measures will limit the spread in hospitals, while social distancing strategies may be necessary to control the outbreak in communities if it remained uncontrolled as in the SARS epidemic.

Hand, foot and mouth disease most commonly occurs in children less than 10 years old, but can occur in immunocompetent adults. We describe a 37-year-old immunocompetent man who presented with multiple painful papules and vesicles on his palms and feet together with vesicles inside the mouth. Real-time polymerase chain reaction revealed Coxsackievirus A6 in the vesicle fluid from the feet, throat swab, and rectal swab. Since the disease is highly contagious, to contain the infection it is prudent to recognise that hand, foot and mouth disease can occur in immunocompetent adults.

Pneumocystis colonization has been associated with airway inflammation and obstruction. We conducted a retrospective cohort study to investigate the clinical significance of Pneumocystis in the airway of patients with active tuberculosis. Of the 108 respiratory specimens tested positive for M. tuberculosis by polymerase chain reaction (PCR), 11 (10.2%) were also positive for Pneumocystis by PCR. Compared with patients tested negative for Pneumocystis, those with Pneumocystis had a higher serum alanine transaminase level, a greater likelihood of requiring oxygen supplementation, and a worse 30-day mortality. The proportion of patients with chronic obstructive pulmonary disease was not significantly different between the 2 groups, but lung malignancy was more prevalent among patients with Pneumocystis. Multivariate analysis showed that Pneumocystis was independently associated with oxygen supplementation. Our study has shown an association between the detection of Pneumocystis in lower respiratory tract specimens and greater impairment of pulmonary function among patients with active tuberculosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We report a case of strongyloidiasis in a patient born in Hong Kong and was possibly infected via her prior occupation in conservancy services. She presented with chronic diarrhoea, anorexia, and extensive scratch marks over the lower extremities. Further assessment yielded eosinophilia, intermittent dyspepsia, and an episode of unexplained Clostridium perfringens bacteraemia. She was treated with a course of albendazole. Subsequently, the eosinophilia and diarrhoea subsided.

Background: We hypothesized that low dose intradermal vaccination of the trivalent influenza vaccine (TIV) delivered by the MicronJet600™ (NanoPass Technologies, Israel) would be non-inferior to the full dose intramuscular and mid dose Intanza(®) vaccination in the elderly and the chronically ill adults., Methods: We performed a prospective randomized trial on elderly and chronically ill adults. Subjects were randomly assigned into 4 groups. Groups ID3 and ID9 received reduced dose ID TIV (3 μg and 9 μg of hemagglutinin (HA) per strain respectively) delivered by MicronJet600™ (NanoPass Technologies, Israel). Group INT9 received reduced dose ID TIV (9 μg) delivered by Becton Dickinson's Soluvia™ device (Intanza(®)9, Sanofi-Pasteur, France). Control group IM15 received a full dose IM TIV (15 μg). We measured antibody titers by hemagglutination inhibition (HAI) and microneutralization (MN) assays at baseline and day 21., Results: Baseline characteristics for all groups were similar (group and sample sizes: ID3=63; ID9=68; INT9=65; and IM15=66). At day 21 post vaccination, the GMT ratio and the seroconversion rates difference for all three strains of the ID vaccine groups were non-inferior to the IM vaccine group. The seroconversion rate, seroprotection rate, and the GMT of the H1N1 strains by HAI and MN assays were significantly higher in the ID groups compared with the full dose IM vaccine group. The seroconversion rates of the H3N2 strain by HAI assay were also significantly higher in the ID groups when compared with the full dose IM group. Direct comparison among the three ID groups showed no significant differences. No serious adverse events related to vaccination were reported., Conclusion: Dose-sparing ID TIV can overcome reduced immunogenicity of the H1N1 strain, and according to some measures, for the H3N2 strain. At risk subjects indicated for the TIV should be considered for intradermal immunization to compensate for reduced immunogenicity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The role of X chromosome-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) in mediating apoptosis has been reported but the underlying mechanism remains unclear. The present study was designed to examine the putative interaction between XAF1 and p53 and the functional importance of this interaction in regulation of apoptosis in human gastric and colon cancer cells. We first identified XAF1 as a novel target gene of p53 by the chromatin immunoprecipitation (CHIP) assay and demonstrated that wild-type p53, but not mutant p53, down-regulated XAF1 at both mRNA and protein levels, which acted mostly under the condition of high expression of XAF1 and was associated with the physical interaction between p53 and the XAF1 promoter. We also found that the over-expression of XAF1 led to activation of wild-type p53 via post-translational modification in cells with or without DNA damage, which resulting in p53 nuclear accumulation and its increased transcriptional activity and enhancing p53-dependent apoptosis. These findings suggest that a potential novel feedback loop exists between XAF1 and wild-type p53., (Copyright © 2011 Wiley Periodicals, Inc.)

Recipients of influenza A (H1N1) vaccine in 1976 had an increased risk for the neurologic disorder Guillain-Barré syndrome (GBS). Anti-ganglioside antibodies, which might be associated with the development of GBS, were previously reported to be induced in mice immunized with an H1N1 vaccine of 1976 or another influenza vaccine. In this study we analyzed anti-ganglioside antibodies in human subjects infected with or vaccinated against 2009 pandemic H1N1, including eight patients diagnosed to have post-vaccination GBS. Antibodies against GM1 or another ganglioside were not detected in any subject or in vaccinated mice. Our results did not support the induction of anti-ganglioside antibodies by influenza viruses or vaccines., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), which plays a crucial role in cancer metastasis. We previously demonstrated that four and a half LIM protein 2 (FHL2) inhibited E-cadherin expression and promoted invasive potential and EMT in colon cancer. Here, we aim to further define the mechanism underlying the inhibition of E-cadherin by FHL2 in colon cancer. The expression profiles of FHL2 and Snail1 were first observed by Western blot, immunofluorescence and immunohistochemistry. We found that both the protein level and the cellular localisation of Snail1 were quite similar to FHL2 in colon cancer; reciprocal co-immunoprecipitation assay showed that FHL2 was able to bind Snail1 and its intact structure was required. The expression of FHL2 was positively correlated to Snail1 while negatively to E-cadherin and phospho-Snail1. FHL2 over-expression induced the accumulation of Snail1 in the nucleus. Moreover, dual luciferase assay revealed that FHL2 over-expression decreased while FHL2 siRNA increased the transcriptional activities of two E-cadherin promoter constructs which contained E-box sites (Snail1-binding elements). Mutation of E-boxes increased the transcriptional activities and FHL2 expression was involved in the function of mutation. These results suggested that FHL2 negatively regulated E-cadherin transcriptional activity through interaction with Snail1. Our study established a novel regulatory function of FHL2 and revealed a potential mechanism on promoting the process of EMT., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: To ensure a good preparedness for pandemic influenza A (H1N1), a study was conducted to investigate clinical effectiveness of hyperimmune intravenous globulin (H-IVIG) prepared from convalescent plasma donated by recovered patients. This article reports on the outcome of the collection phase of the study., Study Design and Methods: Starting on August 26, 2009, all confirmed patients aged between 18 and 55 years were invited for participation into the study and screen for plasma donation eligibility. Effective September 17, 2009, those who were unwilling to consider screening for plasma were asked to donate whole blood. Plasma collected or separated from whole blood had to demonstrate sufficient neutralization antibodies titers of 40 or more before being channeled for H-IVIG production., Results: By October 31, 2009, a total of 9101 persons were successfully contacted. A total of 1309 screening and 619 whole blood donation appointments were made. In the former 786 (60.0%) attended screening but only 301 could donate plasma by apheresis because of failure to meet blood donation eligibility criteria, failed laboratory tests, insufficient neutralization antibody titers, and inability to make the apheresis appointment. For those who opted for whole blood donation, 379 (61.2%) had attended and donated. A total of 276 L of convalescent plasma with sufficient neutralization antibodies titers was collected for H-IVIG production., Discussion: The study highlighted a number of practical limitations in convalescent plasma collection programs and plasmapheresis is always the preferred mode of collection. It provided valuable learning experience for the blood transfusion service in future planning when large-scale collection is required., (© 2010 American Association of Blood Banks.)

Colorectal cancer (CRC) is the second most common lethal cancer in the Western world. There is a 10 to 20 years lead time from normal mucosa to carcinoma which offers a window of opportunity to modify and prevent the outcome of CRC, with its incipient morbidity and mortality. The objective of this paper is to review the evidence for chemoprophylaxis in CRC, identify currently used agents and determine their role in the current management algorithm of CRC. Large cohort-control and randomised controlled trials in the most studied chemoprophylaxis agents are reviewed. Currently, the role for chemoprophylaxis in CRC remains a niche area, with celecoxib the only recommended agent for use in patients with familial polyposis syndromes. However, the role of chemoprophylaxis is likely to grow significantly in the next decade as understanding of the stepwise tumorigenesis cascade becomes better understood and current clinical trials are completed.

Viral shedding profile of infections caused by the pandemic H1N1 2009 influenza A virus has not been reported. The aim of this study was to determine the viral load in different body sites. Viral loads of pandemic H1N1 virus in respiratory specimens, stool, urine, and serum were determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Respiratory specimens from patients with seasonal influenza were used as historical controls. Initial pre-treatment viral load were compared between these two groups. Serial respiratory specimens from patients with pandemic H1N1 virus infection were obtained for analysis of viral dynamics. Twenty-two pandemic H1N1 cases and 44 seasonal influenza historical controls were included. The mean initial viral load before oseltamivir therapy was 1.84 x 10(8) copies/ml for pandemic H1N1 virus compared with 3.28 x 10(8) copies/ml in seasonal influenza historical controls (P = 0.085). Among patients with pandemic H1N1 virus infection, peak viral load occurred on the day of onset of symptoms, and declined gradually afterwards, with no virus being detectable in respiratory specimens by RT-PCR 8 days and by culture 5 days after the onset of symptoms respectively, except in one patient. Pandemic H1N1 virus was detected in stool and in urine from 4/9 and 1/14 patients, respectively. Viral culture was also positive from the stool sample with the highest viral load. Younger age was associated with prolonged shedding in the respiratory tract and higher viral load in the stool. Data from this quantitative analysis of viral shedding may have implications for formulating infection control measures., ((c) 2009 Wiley-Liss, Inc.)

Background: Recent studies have suggested the eradication rate for Helicobacter pylori infection with standard amoxycillin-clarithromycin-containing triple therapy as first-line treatment have fallen below 80%. Levofloxacin-containing triple therapy was proposed as an alternative. The aim of this study is to compare the efficacy and tolerability of the standard 7-day clarithromycin-containing triple therapy against the 7-day levofloxacin-containing triple therapy, and to assess whether the classical triple therapy is still valid as empirical first-line treatment for H. pylori infection in Hong Kong., Methods: Three hundred consecutive H. pylori-positive patients were randomized to receive either 1 week of EAL (esomeprazole 20 mg b.d., amoxycillin 1 g b.d., and levofloxacin 500 mg daily) or EAC (esomeprazole 20 mg b.d., amoxycillin 1 g b.d., and clarithromycin 500 mg b.d.). H. pylori status was rechecked by (13)C-urea breath test 6 weeks after treatment. Patients who failed either of the first-line eradication therapy were invited to undergo H. pylori susceptibility testing., Results: H. pylori eradication was achieved in 128 of 150 (85.3%) patients in EAL and 139 of 150 (92.7%) patients in EAC groups, respectively (p = .043), for both intention-to-treat and per-protocol analysis. More patients in the clarithromycin- than the levofloxacin-containing therapy group developed side effects from the medication (21.3% vs 13.3%, p = .060). Nine patients (six from the EAL group and three from the EAC group) who failed their corresponding eradication therapy returned for susceptibility testing. All nine isolates were highly resistant to levofloxacin (minimum inhibitory concentration or MIC > 32 microg/mL), whereas only two of the six isolates from the EAL group were resistant to clarithromycin (MIC > 0.5 microg/mL)., Conclusions: The standard 7-day clarithromycin-containing triple therapy is still valid as the most effective empirical first-line eradication therapy for H. pylori infection in Hong Kong, as prevalence of primary resistance of H. pylori to amoxycillin and clarithromycin remains low. Patients who failed their empirical first-line eradication therapy should undergo H. pylori susceptibility testing to guide further treatment.